Uncharted territory: bivalirudin and the new P2Y12 inhibitors

Earlier this week, we were discussing the evidence to support the direct thrombin inhibitor (DTI) bivalirudin in patients undergoing percutaneous coronary intervention (PCI) and how its use has evolved to include the full spectrum of acute coronary syndromes (ACS) [1-4]. In general, when compared to the combination of unfractionated heparin (UFH) and a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin is associated with similar ischemic outcomes but a lower incidence of bleeding. Given the poor outcomes associated with bleeding after ACS, these characteristics have conferred a very advantageous benefit-risk profile for bivalirudin in the setting of PCI.

One of the only disadvantages associated with the use of bivalirudin monotherapy is the potential for early stent thrombosis, a phenomenon mostly noted in HORIZONS-AMI, which specifically enrolled patients with ST-segment elevation myocardial infarction receiving early PCI [3]. Although patients randomized to bivalirudin experienced a benefit in net clinical adverse events (9.2% vs. 12.1% with UFH plus GPI, p = 0.005), an increase in stent thrombosis in the first 24 hours was also observed (1.3% vs. 0.3% with UFH plus GPI, p < 0.001). Despite this early difference, rates of stent thrombosis at 30 days were not different between the two groups.

The most plausible explanation for the early increase in stent thrombosis observed in the bivalirudin group is that many patients were probably not yet experiencing the antiplatelet effects of clopidogrel. Although the onset of action is thought to occur more quickly (around 2 hours) with the 600 mg loading dose, only about two-thirds of patients received this dose prior to PCI.  Even at 2 hours, patients randomized to bivalirudin likely experienced a delayed onset of dual antiplatelet therapy compared to those in the UFH plus GPI group, where the onset of GPI therapy would have been almost immediate.

Despite this potential disadvantage with the use of bivalirudin, the overall net clinical benefit still weighs heavily in its favor, so current practice guidelines recognize it as being an acceptable alternative to heparin (with or without a GPI) in patients undergoing PCI [5]. As a result, bivalirudin has largely supplanted the use of heparin at our institution, as well as many other large PCI centers.

However, as we have also expanded our use of the newer P2Y12 inhibitors prasugrel and ticagrelor, the thought occurred to me that these two agents have not been extensively studied with bivalirudin. In fact, I was astounded by how little bivalirudin was used in the landmark trials comparing prasugrel and ticagrelor to clopidogrel -- only 3% and 2% in TRITON TIMI 38 and PLATO, respectively [6, 7].

Given the proposed advantages of these agents compared to clopidogrel (e.g., earlier onset of action, greater potency, no susceptibility to genetic polymorphisms, etc.), one would anticipate that they be at least non-inferior in terms of ischemic outcomes, but do we really know? Prasugrel demonstrated a clear difference in efficacy after only a few hours in its comparison to clopidogrel, but some have attributed at least some degree of this difference to the lower loading dose and delayed administration of clopidogrel in TRITON TIMI 38 [6]. Similar early differences were not observed with ticagrelor, where nearly half of patients were receiving clopidogrel prior to randomization and of those randomized to continue receiving clopidogrel, more received an appropriate loading dose prior to PCI [7]. Interestingly, a recent study of the pharmacodynamic effects of prasugrel and ticagrelor demonstrated that both had fairly poor antiplatelet activity in the hours following an initial loading dose, which makes me wonder just how much of a clinical advantage they provide in the hours immediately following an ACS [8].

Therefore, should we anticipate improvements in the incidence of stent thrombosis and other thrombotic complications when the new P2Y12 inhibitors are used in combination with bivalirudin? More importantly, are these agents associated with similar rates of bleeding as clopidogrel and bivalirudin (at least when compared to UFH plus a GPI)? While one might anticipate comparable rates of bleeding between clopidogrel and ticagrelor (based on similarities observed in the overall trial), I am not sure we can anticipate this with prasugrel given its higher rates of bleeding and fatal bleeding compared to clopidogrel at baseline.

Based on the increased uptake of bivalirudin and the new P2Y12 inhibitors, the combination of the two will undoubtedly become a standard of care -- but is it one that we have robustly tested? While I certainly do not believe we are putting patients at excessive risk with the combination of bivalirudin and a newer P2Y12 inhibitor, I am not sure we have much evidence to support it -- and if there is one thing I have learned from practicing in cardiology, it is that placing faith over evidence is one of the quickest ways to get burned.

References

1. Lincoff AM, Bittl JA, Topol EJ, et al; for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003 Feb 19;289(7):853-63.
2. Stone GW, McLaurin BT, Ohman EM, et al; for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006 Nov 23;355(21):2203-16.
3. Stone GW, Witzenbichler B, Mehran R, et al; for the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008 May 22;358(21):2218-30.
4. Kastrati A, Neumann FJ, Mehilli J, et al; for the ISAR-REACT 4 Trial Investigators. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med. 2011 Nov 24;365(21):1980-9.
5. Levine GN, Bates ER, Ting HH, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011 Dec 6;58(24):e44-e122.
6. Wiviott SD, Braunwald E, Antman EM, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15.
7. Wallentin L, Becker RC, Thorsén M, et al; for the PLATO investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.
8. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) Primary PCI Study. J Am Coll Cardiol 2013; 61: 1601-1606.

CURRENT-OASIS 7: finally time to abandon high-dose aspirin?

Much of the press garnered by the CURRENT-OASIS 7 trial has focused on the comparison of double-dose and standard-dose clopidogrel in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes. The subgroup of patients who actually went to PCI had better outcomes with double-dose clopidogrel, a result that was largely driven by a reduction in recurrent myocardial infarction (MI) and stent thrombosis. Although there was little risk associated with double-dose clopidogrel, the practice only made its way into the 2011 guidelines as a Class IIb recommendation and has not really caught on here at our institution.

Clopidogrel aside, I feel one of the more compelling aspects of the trial was the comparison of high and low-dose aspirin. All patients were initially loaded with high-dose aspirin but were then randomized to receive high-dose (> 300 mg) or low-dose (< 100 mg) aspirin for the remainder of the trial. As expected, there were no differences in efficacy between the two arms... but surprisingly, there were no differences in the rates of bleeding either.

The results of the aspirin analysis in CURRENT-OASIS 7 only reinforce what observational data have suggested for some time -- that higher doses of aspirin are unlikely to provide any additional benefit after an initial loading dose. However, in North America, we tend to use higher doses of aspirin than our counterparts in the rest of the world. (This is thought to be a possible explanation for the North American anomaly seen in the PLATO trial, where patients in North America who received ticagrelor actually did worse than patients across the globe).

With our understanding that the bleeding risk of aspirin is dose-related -- and now with prospective data showing no advantages with the higher dose -- it is surprising that we have not been more proactive in using lower doses here in the US. In fact, while the 2011 guidelines recognize the results of the CURRENT-OASIS 7 trial, they still recommend using higher doses for a period of time in most patients. I recognize that, for the purposes of making it a stronger recommendation, we probably need more data from randomized controlled trials, but these results seem to only confirm something that has been suspected for a long long time (and what many of our European counterparts are already doing).

So, is it time to finally abandon the practice of using high-dose aspirin in patients who receive an appropriate initial loading dose? I think CURRENT-OASIS 7 tells us yes... but until the guidelines change significantly, I imagine many of us here in the US will still feel compelled to use higher dose aspirin for some length of time after an acute coronary event.